WO1990006920A1

WO1990006920A1 - Vinylthiazole derivative and leukotriene antagonist containing the same as active ingredient

Info

Publication number: WO1990006920A1
Application number: PCT/JP1989/001273
Authority: WO
Inventors: Yoshio Hayashi; Tomei Oguri; Rikizo Furuya; Masaki Shinoda; Harumi Nouka; Noboru Yamada
Original assignee: Mitsubishi Kasei Corporation
Priority date: 1988-12-22
Filing date: 1989-12-18
Publication date: 1990-06-28
Also published as: JPH02169584A

Abstract

This invention relates to a vinylthiazole derivative represented by general formula (I), pharmaceutically acceptable salts thereof, and a leukotriene antagonist containing the same as the active ingredient. In the said formula, R' represents a hydrogen atom or a C1 to C5 alkyl group; R?2 and R3¿ each represents a hydrogen atom, a C¿1? to C5 alkyl group, a phenyl group which may be substituted, or a phenylalkyl group which may be substituted on the benzene ring provided that R?2 and R3¿ should not be hydrogen atoms at the same time, or alternatively R?2 and R3¿ may be combined with each other to form a cyclopentane or cyclohexane ring; R?4 and R5¿ each represents a hydrogen atom, a C¿1? to C5 alkyl group or a phenyl group which may be substituted, or alternatively R?4 and R5¿ are combined with each other to form a butadienylene group, (a) wherein R?6, R7, R8 and R9¿ each represents a hydrogen atom, halogen atom, C¿1? to C5 alkyl, C1 to C5 alkoxy, carboxyl, C2 to C6 alkoxycarbonyl, C2 to C5 acyl, amino, cyano, C2 to C5 acylamino or nitro group; and n is an integer of 0 to 5.

Description

Light

[Title of Invention]

Vinylthiazole derivative and leukotriene antagonist containing the same as active ingredient [Technical field]

The present invention relates to a specific vinyl thiazole derivative and a pharmaceutically acceptable salt thereof, and an oral icotriene antagonist containing the compound as an active ingredient.

[Background technology]

To prevent or treat allergic diseases, there are a method of inhibiting the release of the anaphylaxis medium and a method of causing an antagonist to act on the released medium. Disodium chromoglycate [The Merck Index, 9th edition, 2585 (1976)] and tranilast [Nihon Pharmaceutical Journal, 74, 699 (1978)] are representative drugs belonging to the former. The latter include drugs that antagonize histamine, which is one of the mediators of the allergic reaction, such as diphenhydramine, chlorfeniramine, astemizol, terfenadine, and clemastine. Are well known. However, it has been suggested that a substance that is not antagonized by antihistamines, that is, SRS (Slow Reacting Substance), is released from the lungs of bronchial asthma patients, suggesting that “Progress. Allergy, 6, 539 (1962)], recently, the SRS [leuco preparative Lin C ₄ (LTC _4), referred to as SRS collectively Roy co tri E emissions D ₄ (LTD ₄₎ and the mouth I co-triene E ₄ (LTE ₄₎ (Proc. Natl. Acal. Sci. USA), 76, 4275 (1979) and, 2014 (1980); Nature (Nature) , 285, 104 (1980))] is considered to be an important factor involved in human asthma attacks (Proceding of National Academy of Sciences, _proc . Natl. Acad. Scad. USA ), 80, 1712 (1983)].

Several leukotriene antagonists are known in the patent or in the literature. For example,

The following formula:

FPL-55712 [Agents and Actions, 9, 133 (1979)],

The following formula:

KC-404 [Japanese Journal of Pharmaceuticals

― (Jap. J. Pharm.), 33, 267 (1983)], Next formula

ONO-1078 shown by [Synthetic Organic Chemistry, 45 (2), 136 (1987)]

The following formula:

LY-171883 [Pharmacol. Exp. Ther., 233 (1) 1 ^ (1985)], etc., known as No practical examples have been reported.

The present inventors have already obtained the following formula:

[In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, and R ² and R ³ each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, It may have an alkoxyl radical or a substituent. R ² and R ³ are taken together to form a tetramethylene group or _ C = C-C = C-(wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently R ⁴ R ⁵ R ⁶ E

And represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkoxy group, a carbonyl group, or a straight-chain or branched lower alkyl group having 1 to 3 carbon atoms. ) May be formed. And n represents an integer of 2 to 5. It has been found that the thiazole derivative represented by〗 and a pharmaceutically acceptable salt thereof have a leukotriene antagonistic activity (Japanese Patent Application Laid-Open No. 62-142168). IC ₅₀ values are Atsuta in about 10 · ⁵ Μ in in vitro.

Thus, the present inventors have searched for a compound that has a stronger leukotriene anti-action and is effective as a therapeutic agent for various diseases caused by oral triene, and as a result, the present invention relates to a novel compound having an X-substituted carboxyl group. The present inventors have found that a vinylthiazole derivative has an excellent leukotriene antagonistic effect, and have completed the present invention.

[Disclosure of the Invention]

The present invention has the following general formula (I):

WOOC

(In the above formula, R ¹ represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 5 carbon atoms, and R ² and R ³ each independently represent a hydrogen atom, a carbon atom having 1 to 5 carbon atoms. Straight-chain or branched alkyl groups, having substituents Furthermore, the forces R ² and R ³ representing a phenyl group or a phenylalkyl group which may have a substituent on the benzene ring are not simultaneously hydrogen atoms. R ² and R ³ may be combined to form a cyclopentane ring or a cyclohexene ring. R ⁴ and R ⁵ each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent; _ C = C-C = C-(where R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently R ⁶ R ⁷ R ⁸ R ⁹

Hydrogen atom, halogen atom, linear or branched alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 6 carbon atoms, 2 carbon atoms Represents an acyl group, an amino group, a cyano group, an acylamino group having 2 to 5 carbon atoms, or a nitro group having 5 to 5 carbon atoms. ) May be formed. And n represents an integer of 0 to 5. ), Pharmaceutically acceptable salts thereof, and oral triene antagonists containing the compound as an active ingredient. Hereinafter, the present invention will be described more specifically. The range of the compound included in the general formula (I) is not limited by the following specific examples.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may be a straight-chain or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group, Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl Group, t-butyl group, n-pentyl group, i-pentyl group, t-pentyl group and the like. Examples of the phenyl group which may have a substituent and the phenylalkyl group which may have a substituent on a benzene ring which may be included in R ² and R ³ include phenyl, benzyl and phenylethyl. Group, phenylpropyl group, phenylbutyl group, etc., and the substituent on the benzene ring is a lower alkyl group such as methyl group, ethyl group, n-propyl group; chlorine atom, bromine atom, fluorine atom, etc. A lower alkoxy group such as a methoxy group, an ethoxy group or an n-propoxy group; a lower alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group; a carbonyl group; a hydroxy group; Amino groups; cyano groups; lower acetylamino groups such as acetylamino, propionylamino and the like. Carbons which may be contained in R ⁶ , R ⁷ , R ⁸ and R ⁹ Examples of the alkoxy group of rice A 1 to 5 include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy. Group, t-butoxy group, n-pentyloxy group, and the like. Similarly, the alkoxycarbonyl group having 2 to 6 carbon atoms includes methoxycarbonyl group, ethoxycarbonyl group, and n-propoxy group. Reporto, nil group, i-propoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group and i-pentyloxycarbonyl group, and the like. Examples of the acetyl group include an acetyl group, a propionyl group, an n-butyryl group, an i-butyryl group, an n-pentanoyl group and an i_pentanoyl group, and an acetylamino group having 2 to 5 carbon atoms. Examples of the group include an acetylamino group, a propionylamino group, an n-butylylamino group, an i-butyrylamino group, and an n-pentanoylamino group.

Examples of the substituent of the substituted phenyl group which may be included in R ⁴ and R ⁵ include a halogen atom such as a chlorine atom, a bromine atom and a fluorine atom; a hydroxyl group; a methoxy group, an ethoxy group and an n-propoxy group. A lower alkoxy group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group and an n-butyl group; a lower alkoxy carboxy group such as a methoxycarbyl group and an ethoxycarbonyl group; A carboxyl group; an amino group; a nitro group; a cyano group; an acetylamino group such as an acetylamino group and a propionylamino group;

Among the compounds represented by the above general formula (I), preferred are those in which the position of two substituents on the benzene ring is the meta position, and the positional relationship of the substituents at both ends of the ethylene double bond. A compound that is an antigen (E).

The vinylthiazole derivative of the present invention is not limited to a specific isomer, but includes all geometric isomers, optical isomers, and mixtures thereof, for example, racemates.

The vinylthiazole derivative of the present invention can be synthesized by various methods. For example, it can be synthesized by a synthesis route shown in the following reaction formula-1. Reaction formula-:

ROOC

(Π) (HI)

da)

(lb)

The above reaction formulas R ² , R ³ , R ⁴ , R ⁵ and n are as defined in the above general formula (I), and R represents a lower alkyl group.

That is, by reacting the benzaldehyde derivative (II) with 0.8 to 2 equivalents of the 2-methylthiazole derivative (III) and 0.5 to 2 equivalents of the lower fatty acid anhydride to cause a dehydration condensation reaction, the vinylthiazole derivative ( la). Acetic anhydride, propionic anhydride, n-butyric anhydride and the like are used as lower fatty acid anhydrides, and high boiling solvents such as xylene, dimethyl sulfoxide and dimethylformamide can be used as reaction solvents, but none. The reaction may be performed with a solvent. The reaction temperature is room temperature to 250 ° C, preferably 110 to 180 ° C. The vinylthiazole derivative ( _Ia) can be converted into _a vinylthiazole derivative (Ib ₎ by hydrolyzing the ester product by a conventional method. This hydrolysis step can be easily carried out in an aqueous organic solvent such as aqueous ethanol using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, at a temperature within the range of o ° c to the boiling point of the solvent. Can be.

The compound (I) of the present invention has a remarkable leukotriene antagonistic action. That is, when the compound of the present invention was tested in vitro for antagonism to SRS using isolated guinea pig ileum, it was found that the compound of the present invention had selective antagonism to SRS even at low concentrations. found. Therefore, the compound of the present invention is useful for various diseases caused by leukotriene, for example, allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, cerebral vasospasm, or angina caused by reduced coronary blood flow. Etc. are effective for prevention and / or treatment.

The leukotriene antagonist of the present invention comprises, as an active ingredient, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, as a solid or liquid pharmaceutical carrier or diluent, that is, an excipient. Included with excipients such as excipients and stabilizers. When the compound has a carboxyl group, preferred salts are pharmaceutically acceptable non-toxic salts such as alkali metal salts and alkaline earth metal salts, for example, sodium salts and potassium salts. Examples include um salt, magnesium salt, calcium salt, and aluminum salt. Ammonium salts, lower alkylamines [eg, triethylamine] salts, hydroxy lower alkylamines [eg, 2-hydroxylethylamine, bis- (2-hydroxylethyl) amine, tris ( Hydroxy Methyl) amino acid or N-methyl-D-glucamine] salt, cycloalkylamine, for example, dicyclohexylamine] salt, benzylamine [eg, N, N'-dibenzylethylenediamine] Suitable non-toxic amine salts such as salts and dibenzylamine salts are likewise preferred. When attention is paid to the basicity of the thiazole ring of the compound of the present invention, preferred salts include hydrochloride, methanesulfonate, hydrobromide, sulfate, phosphate, fumarate, and succinic acid. Non-toxic salts such as salts. Since these salts are water-soluble, they are most suitable for use as injections. In the leukotriene antagonist, the ratio of the therapeutically active ingredient to the carrier ingredient may be varied between 1% and 90% by weight. The oral triene antagonist may be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids. Alternatively, it may be administered intravenously, intramuscularly or subcutaneously as an injection. It can also be used in the form of suppositories, nasal drops, eye drops or inhalants, and used as a topical preparation for rectal, nasal, ocular and pulmonary administration. In addition, it may be used as a powder for injection and prepared at the time of use. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used to prepare the leukotriene antagonists of the present invention. As an excipient used for producing a solid preparation, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, liquids And the like include commonly used inert diluents such as water or vegetable oil. The formulation may contain, in addition to the inert diluent, adjuvants such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin. Solvents or suspending agents used in the preparation of parenteral administration preparations, ie, injections, suppositories, nasal drops, eye drops, inhalants, etc. include, for example, water, propylene glycol, polyethylene glycol Benzyl alcohol, ethyl oleate, lecithin and the like. Bases used for suppositories include, for example, potato fat, emulsifying potato, laurin fat, witepsol and the like. The preparation method of the preparation may be a conventional method.

The clinical dose, when used by oral administration, is, for adults, the compound of the present invention for an adult generally in a daily dose of 0.01 to 丄 OOOmg, preferably 0.01 to: LOOmg. It is more preferable to increase or decrease as appropriate according to the condition, symptom, presence or absence of simultaneous treatment, and the like. The daily dose of the leukotriene antagonist may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently.

When used as an injection, the compound of the present invention is preferably administered continuously or intermittently to adults in a single dose of 0.001 to 100 mg. [Best Mode for Carrying Out the Invention]

Hereinafter, the ability to explain the present invention in more detail based on Synthesis Examples, Examples and Test Examples of reaction intermediates These do not limit the scope of the present invention at all. “IRJ”, “TLC” and “NMR J” in the synthesis examples and examples represent “infrared absorption spectrum”, “thin layer chromatography” and “nuclear magnetic resonance spectrum”, respectively, and are determined by chromatography. The ratio of the solvent described in the column of separation indicates the volume ratio, the solvent in the brackets of `` TLC '' indicates the developing solvent, and `` IRj is measured by the KBr tablet method unless otherwise specified. The unit is cnr ¹ , "The solvent in the katakana of NMR J indicates the measuring solvent, and the unit is s ppm.

Further, the compound numbers described in the examples correspond to the description numbers in Tables 1, 2, 3 and 4.

In Tables 1 and 2, Me, Et, and Pli represent a methyl group, an ethyl group, and a phenyl group, respectively, and 0, m, and p in the column of the substitution position in the tables represent ortho positions, respectively. , Meta position and para position.

Example 1

Synthesis of Compound No. 14

A mixture of 1.05 g of 3- (3-formylphenyl) -1,2-ethylethyl ethyl ester, 1.20 g of 2-methyl-4-t-butylthiazole and 0.40 ml of acetic anhydride was placed on a 170 ° C. oil bath for 48 hours. The mixture was heated and stirred for an hour. After completion of the reaction, the product was extracted with ethyl acetate, dried, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography-(eluent; _n- heptane / ethyl acetate = 50/1 → 15/1) to give 670 mg (yield 44%) of the title compound as an oil. Obtained.

IR Γ cm- ¹ ]; V = 1730, 1505, 1240, 1210, 1130

_{NMR (CDC1 3); 0.90 (} 6H, t) 1.23 (3H, t),

1.37 (9H, s) 1.5- 1.7 (4H, m)

2.89 (2H, s) 1.12 (2H, q),

6.81 (1H, s) 7.05 (1H, d),

7.2- 7.3 (4H, m), 7.40 (1H, d)

Example 2

Synthesis of various vinylthiazole derivatives

In the same manner as in Example 1, the title compounds shown in Table 1 as compound numbers 13, 17, 23 and 24 were obtained.

Example 3

Synthesis of Compound No.12

541 mg of the compound obtained in Example 1 was added to 6 ml of ethanol, 1.4 ml of a 4N aqueous solution of potassium hydroxide was added, and stirring was continued under reflux for 76 hours. After cooling, the pH was adjusted to 2 with 3N-hydrochloric acid, and the product was extracted with toluene. After drying, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-heptane / ethyl acetate = 25/1 → 2/1) to give 164 mg (yield 33%) of the title compound.

mp [° C]; 122.5-123.5 IR [cm-; v = 1710, 1510, 1225, 1135, 950

Example 4

Synthesis of various vinylthiazole derivatives

In the same manner as in Example 3, Table 1 shows that Compound Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 18, 19, 20, 21, and 22 As a result, the title compound was obtained.

Table 1

Compounds 25 to 72 shown in Table 2 below can be synthesized in the same manner as in the above Examples.

Part II:

Five

Tablet manufacturing

1000 g of well-ground vinylthiazole derivative (Compound No. 10), lactose 5900 g, crystalline cellulose 2000 g, low-substituted hydroxypropyl cellulose 1000 g and magnesium stearate 100 g are mixed well and then directly compressed into tablets. An uncoated tablet containing 10 mg of the compound in 100 mg of 1 tablet was prepared. The uncoated tablets were sugar-coated or film-coated to produce sugar-coated tablets and film-coated tablets.

Example 6

Manufacture of force capsules

1000 g of well-ground vinyl thiazole derivative (Compound No. 10), 3000 g of tu corn starch, 6900 g of lactose, 1000 g of crystalline cellulose and 100 g of magnesium stearate was mixed and mixed to prepare a forcepsell preparation containing 10 mg of the above-mentioned compound in 120 mg of 1 force force.

Example Ί

Production of inhalants

5 g of well crushed vinyl thiazole derivative (compound No. 10), 10 g of Panacet 810® (manufactured by NOF CORPORATION) and 0.2 g of sorbitan monooleate are mixed well, and 15.2 mg of each mixture is mixed into 5 ml and枰取of the aerosol aluminum containers, further first container per after the Freon 12 / Freon 114 (1/1 mixture) 84.8m _g was cold fill, 1 injection ΙΟΟμΙ quantification adapter - a and Ritsuke, 1 container 5ml In the above, a metered dose inhaler containing 5 mg of the compound was produced.

Test example 1

SRS antagonism (in vitro) test

The terminal ileum of a male Hartley guinea pig weighing 200 to 450 g was excised, the lumen was washed, and the ileum was placed in a 5 ml tissue bath containing a tie solution containing the following components. I installed it. The ingredients are 136 mM sodium chloride, 2.7 mM chloride chloride, 11.9 mM sodium bicarbonate, 1.05 mM magnesium chloride, 1.8 mM calcium chloride, 0.4 mM sodium dihydrogen phosphate. The glucose is 5.6 mM. The temperature of the solution in the bath was maintained at 37 ° C, and aeration was performed with 95% oxygen / 5% carbon dioxide. To eliminate shrinkage due Hisuta Mi emissions and Asechirukorin, in the above buffer was added 10- ⁷ g / ml of main pyramidal emissions and 5XlO- ⁸ g / ml of § tropine. Isometric measurement is performed using an isotonic transducer (TD-112S, Nihon Kohden) The change in tension in grams was recorded by Recticcoder-1 (RTG-4142, Nihon Kohden). The ileum was passively loaded with a tension of 0.5 g to obtain an ileal contractile response to SRS extracted from guinea pig lung. The level of continuous contraction by one unit of SRS (equivalent to 5 _{ng of} histamine) was used as a control. Various concentrations of the test drug were added to the tissue bath, and the test drug concentration (IC ₅₀ ) at which control contraction was attenuated by 50% was determined as the minimum effective concentration, and the results are shown in Table 3. As a comparative example, the test results of the aforementioned SHS antagonist with FPL-55712 are also shown in the table.

Table 3

Test example 2

LTDA antagonism (in vivo) test

A male Hartley guinea pig weighing 350-500 g was anaesthetized with an airway by a modified method of Konzett-Roessler using an artificial respirator of the herb type under urea under anesthesia. The resistance was measured. _{_{LTD 4 0.1~: L.0 u g /}} kg against the increased airway resistance due to intravenous administration of body weight, and shows suppression rate by oral administration of test drug calculated result of () in Table 4.

Table 4

Test compound: ιΐ J J "Kanaguchi ίΨ ill half Compound No. Dose (mg / kg body weight) (%)

1 1 100

2 0.1 63

3 1 79

5 0.1 98

9 1 100

10 0.1 95

11 0.1 54

12 0.1 70

14 1 51

15 1 100

16 0.1 73

22 1 97 Test example 3

Acute toxicity test

SD male rats 5 weeks old 4 to 5 animals were taken as a group, and the compound of the present invention was suspended orally in a 1% tragrant solution and observed for 5 days to determine the number of deaths. Pointing out toungue

Table 5

[Industrial applicability]

The vinylthiazole derivative of the present invention can be used as a leukotriene antagonist as a leukotriene antagonist, for example, in various diseases involving leukotriene, such as argygic diseases such as asthma, cerebral edema due to cerebral ischemia, cerebral vasospasm or coronary blood flow. It can be used as a preventive and therapeutic agent for angina pectoris due to decrease.

Claims

Call for car H

(1) The following general formula (I):

Blue

(In the above formula, R ¹ represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 5 carbon atoms, and R ² and R ³ each independently represent a hydrogen atom, a carbon atom having 1 to 5 carbon atoms. Represents a straight-chain or branched alkyl group, a phenyl group which may have a substituent or a phenylalkyl group which may have a substituent on a benzene ring, wherein R ² and R ³ are R ² and R ³ may be combined to form a pentane ring at the mouth or a hexane ring at the mouth, and R ⁵ is each independently a hydrogen atom or a carbon atom; Represents a linear or branched alkyl group of the formulas 1 to 5, or a phenyl group which may have a substituent, wherein R ⁴ and R ⁵ are taken together

_C = C-C = C-(wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently water R ⁶ R ⁷ R ⁸ R ⁹ elementary atom, halogen atom, straight chain having 1 to 5 carbon atoms) Or a branched alkyl group, an alkoxy group having 1 to 5 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, an amino group, a cyano group, It represents an acylamino group having 2 to 5 carbon atoms or a nitro group, and may form a bushenylene group represented by). And n represents an integer of 0 to 5. ) And pharmaceutically acceptable vinylthiazole derivatives Salts thereof that can be

(2) The compound according to claim 1, wherein in the general formula (I), the position of the substituent on the benzene ring is a meta position.

(3) The compound according to (1) or (2), wherein, in the general formula (I), the positional relationship of the substituents at both ends of the ethylene double bond is endogen (E).

(4) An oral icotriene antagonist comprising the compound according to claim 1 as an active ingredient.

(5) An oral glycotriene antagonist comprising the compound according to claim 2 as an active ingredient.

(6) An oral glycotriene antagonist comprising the compound according to claim 3 as an active ingredient.